Thiazine and thiazole triazoles

ABSTRACT

TRIAZOLE DERIVATIVES ARE PROVIDED HAVING THE STRUCTURE   1-(R3-(-S-N=)&gt;C-),3-R1,5-R2-1,2,4-TRIAZOLE   WHICH ARE USEFUL AS ANTHELMINTIC AGENTS.

United States Patent 3,767,654 THIAZINE- AND THIAZOLE-TRIAZOLES Rudiger D. Haugwitz, Highland Park, and Venkatachala L. Narayanan, Hightstown, N.J., assignors to E. R. Squibb & Sons, Inc., Princeton, NJ. No Drawing. Filed Sept. 7, 1971, Ser. No. 178,494

Int. Cl. C07d 93/06 US. Cl. 260-243 R 7 Claims ABSTRACT OF THE DISCLOSURE Triazole derivatives are provided having the structure which are useful as anthelmintic agents.

The present invention relates to 1,2,4-triazo1e derivatives having the structure O (RAD-H3 wherein R is lower alkyl or aryl) or heterocyclic containing one, two or three heteroatoms such as N, O and/ or S. The radical NSi is a 5- or 6-membered ring containing 3 or 4 carbon atoms, respectively, wherein the additional 2 or 3 carbon atoms may include an R substitutent other than hydrogen wherein R is lower alkyl or aryl.

The lower alkyl proups represented by the above R groups include straight or branched chain aliphatic hydrocarbon radicals having up to seven carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, heptyl, and the like. The lower alkyl groups can include as substituents any of the aryl groups mentioned below. a

The term aryl includes monocyclic or bicyclic monovalent aromatic ring systems such as phenyl or naphthyl. These aryl radicals can include as substituents halogen, nitro or any of the alkyl groups mentioned herein before.

Where R heterocyclic substituents are present, both R and R represent the same heterocyclic. Examples of R and R heterocyclic groups include thienyl, nitro thienyl, furyl, chlorofuryl, pyrryl, pyridyl, thiazolyl, isothiazolyl, imidazolyl, piperazinyl, alkylpiperazinyl and pyrazinyl. i

The heterocyclic radical may, if desired, be'substituted at a carbon atom with a lower hydrocarbon group such as a lower alkyl radical.

TABLE A \I/ 31 R: R;

1- H H A 2- H H A 3 CoHs Co a I 4 CsHs OH: I

5--.. CaHu CHQS I N c,H.

8--. CgHgS CuHa I J/IS-CH. e U t 1 Compounds of Formula I can be prepared by first converting the triazole -(1*I) into its salt (HI) by reacting-11- N R1 N R1 laz l The above reaction can be brought about in a variety of aprotic solvents such as aromatic hydrocarbons, e.g., benzene, toluene or xylene or ethers such as ethyl ether or glyme, at temperatures ranging from about to about 150 for periods of about one hour to twenty-four hours. A slight excess of the base is desirable; thus the ratio of triazole (II) to base can range from about 1:1 to about 1:2.

The salt (III) is reacted with an aliphatic haloalkylisothiocyanate (IV) to yield thiourea (V) which are its tautomer VI undergoes intramolecular alkylation to form the novel triazoles (I).

The above reactions are outlined below.

Bl LE m Additional routes toward compounds of structure (IV) are described in Houben-Weyls Methoden Der Organischen Chemie, v01. 9, G. Thieme Verlay Stuttgart, 1955.

It is tobe understood that triazoles containing a free imino hydrogen are virtually tautomeric systems and react like tautomeric mixtures of the two possible forms v I 4 Y 1 7 Their reaction products namely the compounds of Formula-I-of the invention'are not necessarily obtained in equal parts but in proportions which differ from compound to compound.

Examples of triazole starting material H which can be employed herein include the following:

TABLE A il 1! N R 1 CH H 2 CsH H 3 CsHsCH: H

5 CAHD 64H:

CHJOC 7 OKs-S- CIH 8 CHfi H 11 CHfi s CHICGHG Examples of aliphatic haloalkylisothiocyanates which can be employed herein include the following:

S CN-CHzCHzBt S CN-CHBCHzCHzOl S CN-OHAFH-Bt 4 The compounds of Formula 1 form physiologically acceptable acid-addition salts with inorganic and organic acids. These acid-addition salts frequently provide useful means-for isolating the products irom reaction mixtures by forming the salt in a medium in which it is insoluble. The free base may then be obtained by neutralization,

e.g., with a base such as sodium hydroxide. Then any other salt may again be formed from the free base and the appropriate inorganic acid. Illustrative are the hydrohalides, especially the hydrochloride and hydrobromide which are preferred, sulfate, nitrate, phosphate, oxalate, tartrate, maleate, fumarate, citrate, succinate, methanesulfonate, benzenesulfonate, toluenesulfonate, and the like.

The triazoles described herein have anthelmintic activity and are useful in the treatment and/or prevention of helminthiasis, a parasitic disease which causes widespread and often serious infection in domesticated animals such as swine, horses, cattle, sheep and goats. In treating domesticated animals, the compounds may be mixed with a nontoxic, edible carrier to form a feed supplement which is then incorporated in the animal feed in the desired concentration, or they may be administered in unit dosage forms which, in the case of large domesticated animals, take the form of boluses, or in the form of a liquid drench. Alternatively, water-soluble salts or a dispersable, wettable powder containing the anthelmintic agent may be added to the drinking water of the animals.

The preferred dosage level for treating a helminth infection will depend to a large extent on the particular triazole compound being employed, on the severity of the infection and on the particular species of animal to be treated. In general, the triazoles exhibit anthelmintic activity when administered to animals in a daily dose of about 50 to about 300 mg. per kilogram of animal body weight: It is preferred to employ in the range of 100-200 mg. per kilogram of body weight per day. The compounds may be given in a single dose or divided into a plurality of smaller doses. If desired, the course of treatment may be extended over a period of days in which case the optimum daily, dose level may be lowered. When the compounds are to be employed primarily as prophylactic agents for the prevention of helminthic infections, the preferred daily dose level is, of course, lower than the therapeutic level is, preferably in the range of about -70 mg. per kilogram of body weight. The triazoles may be incorporated in the animal feeds,'and this method of administration is preferred when the compounds are to be used prophylactically, in which case they are incorporated in the feeds at concentrations such that the animal will consume daily from about 10 to about 70 mg. of triazole per kilogram of body weight.

The means employed for administering these triazoles to animals are not critical, and any of the methods now used or available for treating animals infected with or susceptible to parasitic infections are satisfactory. When these substances are employed therapeutically to treat an established infection, they are conveniently administered in a unit dosage form such as in a capsule, bolus, tablet, or as a liquid drench. It will be noted that all of these methods contemplate oral administration, since this is the most effective method of treating the worm-infested stomach or intestinal tract.

When the triazoles are tobe administered in unit dosage form, capsules, boluses or drenches containing the desired amount of anthelmintic distributed in a pharmaceutically acceptable vehicle are usually employed. There are prepared by intimately and uniformly mixing the active ingredientwith suitable finely divided diluents, suspending agents, fillers, disintegrating agents and/or binders such as starch, lactose, talc, magnesium stearate, vegetable gums and the like. These unit dosage formulations may be widely varied with respect to their total weight and content of anthelmintic agent, depending on factors such as the type of host animal to be treated, the dose level desired, and the severity and type of parasitic infestation. For large animals such as sheep, swine or cattle, boluses weighing up to grams may be used, although it is preferred to employed boluses weighing from 2-10 grams and containingfrom 1 -5 grams of the anthelmintic agent. These boluses, as well as smaller sizetablets, contain binders and lubricants, and are compounded by techniques known in this art. Capsules are readily prepared by mixing the active ingredient 'with a diluent such as starch or lactose and filling into the capsule.

In order to treat infected animals by means of a drench, the triazoles are mixed with a suspending agent such as bentonite and the solid product added to water just prior to administration. The preferred drenches in accordance with this invention contain from about 550% by weight of triazole compound.

The triazoles described herein may also be administered as a component of the feed of the animals or dissolved or suspended in the drinking water. According to the invention, novel feed and feed supplement compositions are provided in which compounds of Formula I above are present as an active anthelmintic ingredient. Such compositions comprise the triazoles intimately dis,- persed in or admixed with an inert carrier or diluent, i.e. one that is nonreactive with respect to the triazole and that may be administered with safety to the animals. The carrier or diluent is preferably one that is or may be an ingredient of the animal ration.

In the feed supplement compositions the active ingredient is present in relatively large amounts. These supplements are suitable for addition to the feed either directly or after an intermediate dilution or blending step. Examples of carriers or diluents suitable for such compositions are solid orally ingestible carriers such as distillers' dried grains, corn meal, citrus meal, fermentation residues, ground oyster shells, Attapulgus clay, wheat shorts, molasses solubles, corn cob meal, edible vegetable substances, toasted dehulled soya flour, soybean mill feed, antibiotic mycelia, soya grits, crushed limestone and the like. The anthelmintic agents are intimately dispersed or admixed throughout the solid inert carrier by methods such as grinding, stirring, milling, or tumbling. By selecting proper diluents and by altering the ratio of carrier to active ingredient, compositions of any desired concentration may be prepared. Formulations containing from about 5% to about 50% by weight, and preferably from about 10-30% by weight, of active ingredient are particularly suitable for addition to feeds. The active compound is normally dispersed or mixed uniformly in the diluent but in some instances may be sorbed on the carrier.

Feed supplements are prepared by uniformly mixing the appropriate triazole with the carrier or carriers. Such supplements are added to the finished animal feed in an amount adequate to give the final concentration desired for controlling or treating helirninthiasis by Way of the animal ration. Although the preferred level in feeds will depend on the particular compound being employed, the anthelmintic compounds of this invention are normally fed at levels of O.l02.0% in the feed. One advantageous method of administering the compounds of this invention to animals whose feeds are conveniently pelleted, such as sheep, is to incorporate them directly in the pellets. For instance, triazole is readily incorporated in nutritionally adequate alfalfa pellets (during the pelleting operation) at levels of 0.5 to 5 grams per pound of pellets for therapeutic use, and at lower levels for prophylactic use, and such pellets fed to the worm-infested animals. Alternatively, the triazoles may be incorporated in salt licks or salt blocks at any desired concentration (concentrations of 525% by weight are conveniently employed). Large animals such as sheep, cattle and goats, then receive the anthelmintics with their salt.

The following examples further illustrate and repersent preferred embodiments of the invention:

EXAMPLE 1 1-(2-thiazolin-2-yl)-lH-1,2,4-triazole To a solution of 5.0 g. of 1,2,4-triazole in ml. of dry glyme there is added 3.5 g. of sodium hydride (50% mineral oil dispersion) and the mixture is stirred at room temperature for one hour. Then, there is added 8.4 g. of 2-chloroethylisothiocyanate and the mixture is refluxed for one hour. The solvent is evaporated and Water is added to the residue. The resulting solid is filtered oil, dried and crystallized from ethyl ether to yield 5.0 g., M.P. 9395.

Calcd. for C H N S (percent): C, 38.95; H, 3.92; N, 36.33. Found (percent): C, 38.89; H, 4.15; N, 36.43.

EXAMPLE 2 5,4-dihydro-2(1H-l,2,4-triazol-l-yl)-4H-l,3-thiazine To a solution of 5 g. of 1,2,4-triazole in 150 ml. of dry glyrne, there is added 4.0 g. of sodium hydride (50% mineral oil dispersion). The mixture is stirred at room In accordance with the procedure of the foregoing Examples, substituting the triazole shown in column 1 of Table I below and the aliphatic haloalkylisothiocyanate shown in column 2, the product shown in column 3 is obtemperature for two hours after which there is added 3- 15 tained.

TABLE I Column 1 Column 2 Column 3 N R N R J 1 N N N H i 1 6 Example I number R R Haloalkylisothlocyanate R R RI 3 H H SUN-CHflEHCl Asln Column 1 CaHn CaHn- 4 C0115 CH3 SON-CHz-CHzB! -d0 i l 5 01H; H SUN-(311011101 d0 I 6 CH3 CH1 SUN-CHzCHsCl -.-..d0 I

7 CaH1S CeHs SON-CHaCHaBr .do Same as above.

8 H H SON-CHQCHICI d0 Do.

U aHs 0 C 9 OH5CzH4 H SC N(|l HCHr-Br do I 10 C4Hi0 H SON-CHflCH2C1 -do I {\Iiq 11 CIHECH} ClHBG H: SCNCHaCHzCl '----do Same as above.

12 p-CaHy-(HH; CH5 SCNCH'gCHzCIhBl .....-d0 A 13 04H; CHaS SONCEhCHsCHgCl .-.d0..-.: Same as above;

TABLE IContinued Column 1 Column 2 Column 3 N-[\IR N R1 I l N t R \N/ H A x/ 1 j Example 1 number R1 R Haloalkylisothiocyanate R1 R2 R3 14 H H s CNCHzCHzCHBr do I CcHs s CGHQU 15 05H 7 E SCNCHzCHgCHCl do Same as above.

caHs l6 H SCNCHiCHflCHjBI do CH;0C A

17 SONCHzCIEhCl do I N l I! IL A, U

18 I H S CNCHgCHgBI :.-:..do...-.;.'.....:- Same as above;

19 SCNCHzCHqCHzCl do l N N N 20 I I S CNCHflCHlCHZBl do Same as above.

What is claimed is: represents a 5 or 6 membered ring; aryl is a monoor bi- 1. A compound of the structure: carbocyclic aromatic ring system of 6 to 10 carbon atoms; and physiologically acceptable acid-addition salts thereof. R1 2. A compound as defined in claim 1 having the structure 1 A Il L N U 3. A compound as defined in claim 1 having the structure N-H R1 1 1 1 2 4. A compound as defined in claim 1 having the struc- 7. A compound as defined in claim 1 having the structure ture "Fa L 5 N N N s 5. A compound as denfied in claim 1 having the struc- U m A U ture N S References Cited UNITED STATES PATENTS 2,577,409 12/1951 Emerson et a1 260243 6. A compound as defined in c aim 1 having the t 3,499,083 3/1970 Levitt 260243 X C FOREIGN PATENTS H H 1,253,002 11/1971 Great Britain 260243 N \N/ JOHN M. FORD, Primary Examiner A US. 01. xn.

i 260306.7, 308 R, 296 R; 424-246, 270

1; "IIIIED STATES I MEN: bFFICE, TE OF CORRECTION Dated" October 23 1973 Rudiger D. Haugwitz, Venkatachala LY. Narayanan is sertified that error appears in the above-id and C512: said Lett l ified ars Pa-.ant are hareny corrected as she Patent n below:

Column 3, lines 70 to 75, ,formula A, that portion reading: I 1

should be: u, 7

. N I H Column 5, line 61,. "There should be: These Column 9, Table 1, Column 1, that portionof the formula reading:

Column 10, Table 1, Column 3 Example 17, that portion "of the Signed and Seal this of A i .l9'm.,

(SEAL) Attest:

EDWARD ILFLiiITGHEELJR. C. MAR-SHALL DANN' g Attesting Officer Commissioner of Patents 

